Recently, immune suppressant agents have come into prominence because of their use during transplants of organs from one human to another, and in particular in connection with organ transplant operations such as heart and kidney transplants. It is part of the defense mechanism of humans to remove foreign antigens (in this case, produced by the transplanted organ) by the immune reaction. Thus, in all of the organ transplant operations, it has been necessary to give large doses of an immune suppressant prior to the operation and continuing thereafter in order to prevent the host from rejecting the donor organ.
The immune response is composed of a sequence of cellular transformations and biochemical events leading to a bimodal response to foreign substances (antigens). Cells which are to participate in the response evolve from stem cells which originate in the bone marrow and are seeded out to the peripheral lymphoid organs. From these latter sites, following antigenic stimulus, the body's response is mounted in the form of plasma cells (which produce antibody) and specific immune lymphocytes. Antibody is released into the circulatory system and thus may act at a distance from the producing cell (humoral immunity). Specific immune lymphocytes also enter the circulatory system and act at the site of injury (cellular immunity). The reaction of antibody with antigen triggers the release of histamine from basophilic leucocytes; histamine, in turn, alters the permeability of blood vessels, speeding the influx of body antibody and specific immune lymphocytes into the sites of injury. Thus, the immune response is composed of a series of biochemical events in a sequence of cells at various sites in the body. It can be altered--suppressed, in the case of the compounds herein discussed--at a number of biochemical or cellular developmental sites.
Antihistamines only affect a secondary reaction in the immune response, having no direct effect on antibody-producing cells or on specific immune lymphocytes. A number of agents, currently in use as immuno-suppressive drugs, act further back in the chain of events called herein the immune response. Certain anti-inflammatory steroids, e.g., cortisone, suppress production of antibody and specific immune lymphocytes, but also radically deplete normal lymphoid tissue and have other undesirable side effects. Certain anti-neoplastic drugs e.g., azathioprine, cyclophosphamide, and methotrexate, are employed as immunosuppressives, but they also deplete normal lymphoid tissue and radically depress other bone-marrow-derived cells. The general cytotoxicity of the latter drugs is to be expected in view of their having been selected on the basis of toxicity against a spectrum of cell types.
It is an object of this invention to provide compounds which alter the immune response in mammals by acting on cells functioning in the immune response, but which avoid certain side-effects and other undesirable attributes of compounds currently available as immune regulants.
Certain substituted 7H-benzimidazo[2,1-a]benz[de]isoquinoline-7-ones, as named and numbered according to the Ring Index, The American Chemical Society, number 5818, as follows: ##STR1## and their method of preparation are taught in the literature. Okazaki, et. al., J. Soc. Org. Synthet. Chem., Japan, 13, 80, 175, 228, and 413 (1955), describe the preparation of 10- and 11-substituted compounds as represented by Formula I wherein R is hydrogen, methyl, methoxy, and chloro. Similarly, Arient and Marhan, Collection Czech. Chem. Commun., 28, 1292 (1963), describe the synthesis of related compounds wherein R is chloro, methyl, nitro, and amino. Each citation uses the same two methods of preparation. The first method employs the reaction between 1,8-naphthalic acid anhydride and appropriately substituted o-phenylenediamines, the latter either being prepared and isolated or formed in situ from the appropriate o-nitroaniline precursor. The in situ preparation may be done prior to the introduction of the anhydride or in the presence of the anhydride.
The second method produces an intermediate N-substituted-naphthalimide from the reaction of naphthalic anhydride with the appropriately substituted o-nitroaniline, which in a second step can be converted to the final product (i.e., compounds as represented in Formula I) by chemical reduction and condensation.
Both methods were more recently employed in a patent (U.S. Pat. No. 4,097,450) describing the reaction of o-phenylenediamines and o-nitroanilines with 3,6-dihydroxynaphthalic acid anhydride to prepare 2,5-dihydroxy congeners of the compounds represented by Formula I.
In all three citations above it has been recognized that the (second) method utilizing o-nitroanilines is superior to the first method when the corresponding o-phenylenediamine reaction can and does give two isomers. For example, Okazaki (supra, p. 413) demonstrated a 42:58 ratio of 10- to 11-chloro isomers when 3,4-diaminochlorobenzene was reacted with naphthalic anhydride, whereas pure isomers could be obtained when the appropriately substituted o-nitroanilines were first reacted with the anhydride and followed with chemical reduction and condensation.
It has also been taught (Arient and Marhan, supra) how various derivatives, such as where R is chloro, can be prepared from compounds of Formula I where R is nitro, upon reduction to the aniline (R is NH.sub.2) and subsequent transformations via the Sandmeyer reaction.
In the above references the compounds of Formula I were found to possess qualities suitable for their use as dyes and pigments. More recently several derivatives are also said to be useful as epoxy hardeners and as thickening agents for greases.